Assessment of the direct and indirect effects of MPP+ and dopamine on the human proteasome: implications for Parkinson's disease aetiology

Caneda-Ferrón, B, De, Girolamo, Costa, T, Beck, KE, Layfield, R and Billett, EE ORCID: https://orcid.org/0000-0001-8245-6519, 2008. Assessment of the direct and indirect effects of MPP+ and dopamine on the human proteasome: implications for Parkinson's disease aetiology. Journal of Neurochemistry, 105 (1), pp. 225-238. ISSN 0022-3042

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Abstract

Mitochondrial impairment, glutathione depletion and oxidative stress have been implicated in the pathogenesis of Parkinson’s disease (PD), linked recently to proteasomal dysfunction. Our study analysed how these factors influence the various activities of the proteasome in human SH-SY5Y neuroblastoma cells treated with the PD mimetics MPP+ (a complex 1 inhibitor) or dopamine. Treatment with these toxins led to dose- and time-dependent reductions in ATP and glutathione and also chymotrypsin-like and post-acidic like activities; trypsin-like activity was unaffected. Antioxidants blocked the effects of dopamine, but not MPP+, suggesting that oxidative stress was more important in the dopamine-mediated effects. With MPP+, ATP depletion was a prerequisite for loss of proteasomal activity. Thus in a dopaminergic neuron with complex 1 dysfunction both oxidative stress and ATP depletion will contribute independently to loss of proteasomal function. We show for the first time that addition of MPP+ or dopamine to purified samples of the human 20S proteasome also reduced proteasomal activities; with dopamine being most damaging. As with toxin-treated cells, chymotrypsin-like activity was most sensitive and trypsin-like activity the least sensitive. The observed differential sensitivity of the various proteasomal activities to PD mimetics is novel and its significance needs further study in human cells.

Item Type:	Journal article
Description:	The definitive version is available at www3.interscience.wiley.com
Publication Title:	Journal of Neurochemistry
Creators:	Caneda-Ferrón, B., De, G., Costa, T., Beck, K.E., Layfield, R. and Billett, E.E.
Publisher:	International Society for Neurochemistry/Wiley-Blackwell Publishing Ltd.
Date:	2008
Volume:	105
Number:	1
ISSN:	0022-3042
Identifiers:	Number Type 10.1111/j.1471-4159.2007.05130.x DOI
Rights:	© 2007 The Authors
Divisions:	Schools > School of Science and Technology
Record created by:	EPrints Services
Date Added:	09 Oct 2015 09:47
Last Modified:	09 Jun 2017 13:10
URI:	https://irep.ntu.ac.uk/id/eprint/2805

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